The multifactorial nature of disease motivates the use of
systems-level analyses to understand their pathology. We used a
systems biology approach to study tau aggregation, one of the
hallmark features of Alzheimer's disease. A mathematical model
was constructed to capture the current state of knowledge
concerning tau's behavior and interactions in cells. The model
was implemented in silico in the form of ordinary differential
equations. The identifiability of the model was assessed and
parameters were estimated to generate two cellular states: a
population of solutions that corresponds to normal tau
homeostasis and a population of solutions that displays
aggregation-prone behavior. The model of normal tau homeostasis
was robust to perturbations, and disturbances in multiple
processes were required to achieve an aggregation-prone state.
The aggregation-prone state was ultrasensitive to perturbations
in diverse subsets of networks. Tau aggregation requires that
multiple cellular parameters are set coordinately to a set of
values that drive pathological assembly of tau. This model
provides a foundation on which to build and increase our
understanding of the series of events that lead to tau
aggregation and may ultimately be used to identify critical
intervention points that can direct the cell away from tau
aggregation to aid in the treatment of tau-mediated (or
related) aggregation diseases including Alzheimer's.

To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.

Parameters are took from “Run1” of “Disease Params” sheet, on Dataset S1.
To run this plot, the specie “Tau04MT” from Table S1 using the reactions from Table S2 is divided by the specie “Tau04MT” from Table S1 using the reactions from Table S2 including a 5-fold increase in the parameter associated with the binding of normally phosphorylated tau 3R to microtubules (reaction 12).

The simulation was done using Copasi v4.12 (Build 81) and the plots were generated using Gnuplot. The models with simulation settings can be downloaded from the below links:
- Copasi file of “Tau04MT” basal concentration
- Copasi file of “Tau04MT” concentration when 5-fold increase in reaction 12 is implemented

Additional file(s)

Yuraszeck2010 - Vulnerabilities in the Tau Network in Tau Pathophysiology:

Copasi file of “Tau04MT” concentration when 5-fold increase in reaction 12 is implemented